PAR-27-045-Full-Announcement.html

Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Center for Complementary and Integrative Health (NCCIH)

National Institute on Aging (NIA)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute of Neurological Disorders and Stroke (NINDS)

Note: Not all NIH Institutes, Centers, and Offices (ICOs) participate in Announcements. Applicants should carefully note which ICOs participate in this announcement and view their respective areas of research interest at the ICO-Specific Scientific Interests website. ICOs that do not participate in this announcement will not consider applications for funding.

Funding Opportunity Title

HEAL Initiative: Whole Joint Health Program (R61/R33 Clinical Trial Required)

Activity Code

R61/R33 Exploratory/Developmental Phased Award

Announcement Type

New

Related Notices

Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON)

PAR-27-045

Companion Funding Opportunity

None

Number of Applications

See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.473, 93.213, 93.853, 93.273, 93.866, 93.846, 93.121, 93.286

Funding Opportunity Purpose

The NIH Helping to End Addiction Long-term® (HEAL) Initiative is releasing this Notice of Funding Opportunity (NOFO) to support a phased mechanistic clinical research program focusing on understudied biological mechanisms that drive joint pain. The phased projects supported by this program (of up to five years total in duration) will first identify and validate multi-tissue mechanisms underlying joint pain, then test non-pharmacologic or multimodal interventions that directly target these mechanisms. The initiative responds to priorities identified in the 2023 HEAL Whole Joint Pain Workshop and supports the broader goals of the NIH HEAL Initiative and the Make America Healthy Again vision by advancing safe, non-addictive, and prevention-oriented approaches to chronic pain.

Funding Opportunity Goal(s)

NCCIH is the lead Federal agency for scientific research on the fundamental science, usefulness, and safety of complementary and integrative treatments and practices. To address the need for objective evidence on the fundamental science, safety and efficacy of complementary and integrative health approaches, NCCIH supports rigorous scientific investigation to better understand how these interventions impact health, for whom, and the optimal methods of practice and delivery.

Key Dates

Posted Date

September 28, 2026

Open Date (Earliest Submission Date)

September 30, 2026

October 30, 2026

Not Applicable

Not Applicable

July 2027

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Due Dates for E.O. 12372

Not Applicable

Expiration Date

October 31, 2026

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information Key Dates Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background Joint pain is highly prevalent and disabling. It contributes substantially to chronic pain, reduced mobility, and diminished quality of life across the lifespan. Many individuals with joint pain do not achieve lasting relief despite extensive biomedical research and clinical investment. Continued reliance on reductionist approaches, which focus on single tissues or structures rather than on the joint as a dynamic, integrated system, contribute to this major challenge.

This initiative defines the "whole joint" as an integrated organ system. It includes articular tissues such as bone, cartilage, and synovium. It also includes periarticular tissues such as muscle, adipose tissue, ligaments, tendons, and fasciae. Peripheral physiological or neural systems include peripheral nerves, blood vessels, lymphatic structures, and endocrine tissues.

In July 2023, the NIH Helping to End Addiction Long-term® (HEAL) Initiative convened a workshop titled "Understanding and Restoring Whole Joint Health in Pain Management." The workshop assessed the current state of the science and identified critical gaps in joint pain research. Participants emphasized that joint pain arises from complex, interrelated processes involving articular and periarticular tissues. These processes include changes in biomechanics, metabolism, inflammation, neural signaling, and psychosocial influences. Participants acknowledged that researchers have not adequately studied many of these processes. Structural abnormalities identified through conventional imaging often correlate poorly with pain indicating additional factors might be involved. This gap underscores the need to study multi-tissue mechanisms and inter-tissue communication across the whole joint.

Participants also noted that pain prevention and joint restoration are likely to require attention to nutritional, psychological, and physical domains. Effective pain relief may require multimodal approaches, including non-pharmacologic interventions to effectively target multiple tissues and systems that comprise the whole joint. Recent advances now make this work feasible, including new imaging, computational modeling, tissue-specific -omics, and related tools and methods to study myofascial and nerve-tissue interactions. Together, these techniques will allow investigators to examine the joint as a complex organ and to capture dynamic changes associated with pain, healing, and functional recovery.

The goal of this NOFO is to advance the mechanistic understanding of interactions across these tissues and systems that together define the "whole joint" as one integrated organ. As such, this NOFO will support studies that identify and measure whole joint mechanisms, including at least one periarticular tissue and interactions with one or more articular tissues or peripheral physiological or neural systems. This NOFO will support studies that first examine how these interactions contribute to joint pain and reduced whole joint health and then determine how interventions modify mechanisms across multiple tissues and pathways to restore whole joint health.

Research Objectives This two-phase NOFO will support well-powered, hypothesis-driven mechanistic clinical studies aligned with HEAL's whole joint health priorities.

R61 Phase (2 or 3 Years):

In the R61 phase, studies will test innovative whole joint mechanisms in healthy and clinical pain populations to generate strong preliminary data to support the R33 clinical trial. Studies will include one or more observational or mechanistic clinical study(ies) that measure whole joint mechanisms, including at least one periarticular tissue and the interactions with one or more articular tissue(s) and/or peripheral physiological or neural system(s), to demonstrate measurable differences in joint pain and pathophysiology between a clinical population with joint pain versus a healthy population with no joint pain.

This NOFO prioritizes innovation in the proposed measures of whole joint mechanisms. The inclusion of multiple tissues and mechanisms involved in whole joint function as well as joint pain and pathophysiology is considered a strength.

Specific Areas of Research Interest Examples of innovative mechanisms include (but are not limited to):

This NOFO will also support studies that may incorporate innovative or cutting-edge imaging, biomarker profiling, neuromuscular assessment, and/or behavioral or environmental measures. Other multimodal approaches that meet NIH standards for rigor and reproducibility will also be supported.

R33 Phase (2 or 3 Years; Total Project Period 5 Years or less):

The R33 phase supports mechanistic clinical trials to test the effects of non-pharmacologic or multimodal interventions on the proposed mechanisms demonstrated in the R61 phase. The selected intervention and its expected mechanistic impact should be well-justified and coupled with a rigorous clinical trial design. The rationale for the proposed intervention may be based on prior work published in the literature or preliminary data generated in the R61 phase using appropriate models, organisms, or human populations.

Examples of appropriate non-pharmocologic interventions for joint pain include (but are not limited to):

This NOFO will support additional interventions if there is evidence provided supporting its relevance to the joint tissues studied in the R61 phase and if the intervention is likely to produce measurable mechanistic changes. Additional approaches may include devices, drugs, or other multimodal therapies.

Definitions and restrictions for this NOFO:

Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control(s)) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

Applications Not Responsive to this NOFO The following types of applications are not responsive to this NOFO and will not be reviewed:

Studies that assess clinical efficacy/effectiveness of an intervention.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

Funding Instrument

Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New

The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are not limited but need to reflect the actual needs of the proposed project. However, it is strongly recommended that applicants do not request a budget of more than $500k in direct costs per year for the R61 phase. For applications that propose a 3-year R33 project phase, it is strongly recommended that they budget no more than $700k in direct costs per year. For applications proposing a 2-year R33 phase, it is strongly recommended that they budget no more than $800k in direct costs per year.

Award Project Period

The scope of the project should determine the project period for each phase. The maximum period of the combined R61 and R33 phases is 5 years, with 2 or 3 years for the R61 phase and 2 or 3 years for the R33 phase.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Local Governments

Federal Governments

Eligible Agencies of the Federal Government

U.S. Territory or Possession

Other

Independent School Districts

Public Housing Authorities/Indian Housing Authorities

Native American Tribal Organizations (other than Federally recognized tribal governments)

Faith-based or Community-based Organizations

Regional Organizations

Foreign Organizations/International Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

Applicant Organizations Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.

Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide.

2. Cost Sharing This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.

A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

SF424(R&R) Senior/Key Person Profile

R&R Budget

R&R Subaward Budget

Its strongly recommended that applicants budget no more than $500k in direct costs per year for the R61 phase. For applications that propose a 3-year R33 project phase, it is strongly recommended that applicants budget no more than $700k in direct costs per year. For applications proposing a 2-year R33 phase, it is strongly recommended that applicants budget no more than $800k in direct costs per year.

PHS 398 Cover Page Supplement

PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims The Specific Aims page should include a brief description of the following:

The objectives and hypotheses for the R61 and R33 phases should be clearly distinguished using appropriate headers.

Research Strategy Importance of the Research

Background and Research Objectives

Approach In general, the Research Approach must include relevant figures and clear descriptions of the study design and analytic plan for both phases. Applicants should organize the Research Approach to have distinct R61 and R33 phase plans, in separate sections. Quantitative details for the R61-to-R33 transition criteria should be provided in this part of the application, under a separate heading for "Go/No-Go Criteria", as detailed below. Applications should include a clear timeline for completing the R61 phase.

R61 Phase

R61-to-R33 Go/No-Go Transition Provide this information under the heading: "Go/No-Go Criteria for R61."

R61/R33 Go/No-Go Transition Process Transition between the R61 and R33 phases will be guided by clearly defined milestone-based transition criteria. These criteria should allow reviewers to determine whether the R61 phase provides sufficient evidence to proceed to the R33 phase. NIH does not negotiate benchmarks or milestones prior to application submission but may negotiate transition criteria and milestones prior to making an award.

The HEAL program team will review R61-phase progress administratively. NIH will not transition projects to the R33 phase if investigators do not meet the approved Go/No-Go criteria. NIH must approve these criteria before issuing the R61 award.

Note that not all R61 grants will transition to the R33 phase, even if milestones are met. NIH will also consider the quality of the planned R33 clinical trial, the clinical investigator team, available funds, program relevance and priority at the time of transition request.

R33 Phase In the R33 phase, applicants must test the effect of the proposed intervention(s) on the hypothesized mechanistic measure(s) established during the R61 phase. Studies should propose separate clinical cohorts from the R61 phase to achieve a well-powered clinical trial.

Subsequent Studies Beyond the R61/R33 Briefly summarize planned future studies. These studies may focus on clinical efficacy as the primary goal or on further mechanistic investigation.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format. Where the DMS Plan Format Page requires a "Yes or No" response, no additional narrative is allowed.

All HEAL-funded studies must follow the HEAL data sharing requirements. Please refer to the the HEAL Public Access and Data Sharing Policy.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Describe the following: 1) the planned recruitment methods, including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media/social media, and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants.

Applicants must provide strong evidence of the availability of appropriate institutional resources and suitable patient populations. Documentation of the availability of eligible participants must be provided. The application must provide relevant information that addresses the feasibility of recruiting a robust sample of eligible participants.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

In addition to the NIH application requirements for data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH's policy on data and safety monitoring (https://grants.nih.gov/grants/guide/notice-files/not-od-00-038.html).

Section 4 - Protocol Synopsis

4.5. Will the study use an FDA-regulated intervention?

4.5.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status If the proposed clinical trial will use a device, natural product (such as botanicals, probiotics, and products marketed as dietary supplements), or drug, this attachment should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial and associated timeline. For trials using an FDA-regulated product that requires an IND/IDE application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. If the protocol is conducted under a non-U.S. regulatory agency, the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided as part of the PDF file attachment. The FDA has provided guidance indicating that when substances that are Generally Recognized as Safe (GRAS) are used in a clinical trial to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent disease it may require an IND under part 312 (https://www.fda.gov/media/79386/download). If an IND is required by the FDA for the proposed trial, the IND must be submitted to the FDA with no clinical hold imposed by the FDA prior to the application being funded.

Delayed Onset Study Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply- Application Guide must be followed.

PHS Assignment Request Form

3. Unique Entity Identifier and System for Award Management (SAM) See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372) This initiative is not subject to intergovernmental review.

6. Funding Restrictions All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply – Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply – Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Mandatory Disclosure

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

Projects supported by this two-phase NOFO will support well-powered, hypothesis-driven mechanistic clinical studies that align with the HEAL Initiative's whole joint health priorities. Meritorious projects will identify and validate whole joint mechanisms underlying joint pain in the first phase, then test non-pharmacologic or multimodal interventions that directly target these mechanisms in the second phase. Please note that while applications can specify the length of time (two or three years) for each of the following study phases, the total project length cannot exceed 5 years.

High-priority programmatic considerations include, but are not limited to:

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Scored Review Criteria

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score.

Factor 1. Importance of the Research (Significance and Innovation)

Innovation

Specific to this NOFO Evaluate the relevance and importance of the chosen tissue types in advancing knowledge of potential mechanistic targets involved in whole joint pain and pathophysiology.

Evaluate the significance and strength of the scientific rationale related to the non-pharmacologic or multimodal intervention(s) proposed in the R33 study and the potential impact of the intervention(s) on the proposed mechanistic measures developed during the R61 phase.

Factor 2. Rigor and Feasibility (Approach)

Rigor:

For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.

Feasibility:

Specific to this NOFO:

Evaluate how well the hypothesized primary mechanism(s) are described and defined, either based on relevant prior studies or preliminary data, and the appropriateness of the metrics or measures related to the proposed whole joint mechanism(s).

Evaluate the relevance of the populations and associated clinical or functional outcomes to be studied in the R61 and R33 phases to the hypothesized mechanisms and to the proposed intervention.

Evaluate the likelihood that the proposed measure(s) will differentiate healthy whole joint function from clinical joint pain phenotypes during the R61 phase, providing strong preliminary data for the proposed R33-phase clinical trial.

Evaluate if the listed Go/No-Go Transition Criteria are well-justified and well-defined, with specified threshold(s) to differentiate joint pain and/or pathophysiology in a chosen clinical pain population using the proposed measures.

Evaluate how useful the Go/No-Go Transition Criteria (as presented) would be in demonstrating the readiness of the project to advance from the mechanistic study R61 phase to the R33 intervention trial phase.

Factor 3. Expertise and Resources (Investigator(s) and Environment)

Investigator(s) Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.

Environment Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.

Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects; 2) adequacy of protection against risks; 3) potential benefits to the subjects and others; 4) importance of the knowledge to be gained; and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, evaluate: 1) the justification for the exemption; 2) human subjects involvement and characteristics; and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Vertebrate Animals

When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.

Resubmissions

As applicable,…